Journal Article Randomized Controlled Trial Clinical Trial, Phase II Epublish
PubMed: 42039169 DOI: 10.3389/fimmu.2026.1769223
Therapeutic HIV-1 Tat vaccination promotes durable immune reconstitution and reservoir reduction in ART-treated adults with clade C infection: a 12-year follow-up study.
Front Immunol 17:1769223
Authors: Orietta Picconi, Cecilia Sgadari, Antonella Tripiciano, Sonia Moretti, Maria Teresa Maggiorella, Vittorio Francavilla, Anna Casabianca, Chiara Orlandi, Roberto Belli, Clelia Palladino, Massimo Campagna, Flavia Mancini, Leonardo Sernicola, Maria Rosaria Pavone Cossut, Fulvia Pimpinelli, Mauro Magnani, Fabrizio Ensoli, Matsontso Mathebula, Aurelio Cafaro, Paolo Monini, Maphoshane Nchabeleng, Barbara Ensoli
Affiliations
- National HIV/AIDS Research Center, Istituto Superiore di Sanità , Rome, Italy.
- Department of Biomolecular Science, University of Urbino, Urbino, Italy.
- Laboratory of Microbiology and Virology, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.
- Laboratory of Clinical Pathology and Microbiology, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.
- Mecru Clinical Research Unit (MeCRU), Sefako Makgatho Health Sciences University (SMU), Gauteng, South Africa.
- National Health Service, Dr George Mukhari Microbiology Laboratory, Pretoria, South Africa.
Abstract
INTRODUCTION
Antiretroviral therapy (ART) suppresses HIV replication but fails to eradicate viral reservoirs or fully restore immune competence. Therapeutic vaccination targeting HIV-1 Tat, a key viral protein persistently expressed also during ART, may enhance immune reconstitution and limit reservoir maintenance. Long-term data in individuals infected with HIV-1 clade C, particularly in sub-Saharan Africa, are lacking.
METHODS
We conducted a 12-year extended follow-up of 161 ART-treated adults previously enrolled in a randomized, placebo-controlled phase 2 trial of therapeutic HIV-1 Tat vaccination in South Africa (ISS T-003; SANCTR n. DOH-27-0211-3351; ClinicalTrials.gov: NCT01513135). No booster immunizations were administered. Longitudinal outcomes included anti-Tat antibody (Ab) persistence, CD4 + T-cell counts, plasma HIV RNA, and total HIV DNA in peripheral CD4 + T cells. Analyses were stratified by sex and ART adherence.
RESULTS
Ninety-seven percent of vaccinees developed anti-Tat Abs after immunization, and 70% were still positive at the beginning of the extended follow-up (3 years). Among these, 39% maintained Ab responses for their entire observation period (median duration 4 years), and 17 participants (20%) remained anti-Tat Ab seropositive up to year 12. Moreover, both Ab durability and peak titers were greater in vaccinees than in naturally occurring antibodies in seroconverter placebos. Compared with placebo, Tat vaccination was associated with earlier and sustained CD4 + T-cell recovery and accelerated decline of total HIV DNA, effects that persisted for more than a decade. These benefits were most pronounced in men, who were more immunocompromised at baseline, and in individuals with suboptimal ART adherence. Notably, vaccinated participants with intermittent viremia maintained stable or increasing CD4 + T-cell counts and continued reservoir reduction over time.
DISCUSSION
Therapeutic HIV-1 Tat vaccination induces long-lasting immunological benefits that extend beyond viral suppression achieved by ART alone, promoting durable immune reconstitution and progressive reservoir decay in clade C infection. These findings confirm results from a long-term follow-up of a parallel phase 2 trial in Italy, and both support Tat vaccination as a potential ART-intensifying strategy, particularly in populations with advanced immunosuppression or imperfect ART adherence.
TRIAL REGISTRATION
SANCTR n. DOH-27-0615-4948 and ClinicalTrials.gov: NCT02712489; and SANCTR n. DOH-27-072022-7347 and ClinicalTrials.gov: NCT05680948.
MeSH
Cells, Hiv-1, Immunization, Vaccines, Follow-Up Studies, Acquired Immunodeficiency Syndrome, Vaccination, Hiv, Cell Count, Genes, Tat, Immune Reconstitution, Therapeutics, Infections